New Treatments for Lung Cancer in 2016


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With drug approvals for immunotherapy in the first- and second-line settings, breakthroughs in targeting epidermal growth factor receptor (EGFR) mutations, and the rapid evolution of therapies that target anaplastic lymphoma kinase (ALK) rearrangements, 2016 has been an extraordinary year for lung cancer.

At the Cedars-Sinai annual symposium on New Therapeutics in Oncology: The Road to Personalized Medicine, Ronald B. Natale, MD, Medical Director of Lung Cancer Clinical Research Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, summarized the year’s most important clinical advances in lung cancer and described the current standards of care.1

Immunotherapy


There seems to be a very high penetrance of osimertinib into the brain compared to plasma concentrations. The development of osimertinib, a mutation-selective targeted agent, is really a major achievement in medical oncology.
— Ronald B. Natale, MD

In October, based on the results of the phase III KEYNOTE-024 trial presented at the 2016 European Society for Medical Oncology (ESMO) Congress and published in The New England Journal of Medicine, pembrolizumab (Keytruda) was approved for the first-line treatment of patients with advanced non–small cell lung cancer (NSCLC).2 Patients with programmed cell death ligand 1 (PD-L1) expression in at least 50% of tumor cells were randomly assigned to single-agent pembrolizumab vs platinum-based chemotherapy.

Pembrolizumab significantly improved progression-free survival compared to the standard of care (10.3 vs 6.0 months, hazard ratio [HR] = 0.50). Overall survival in the intent-to-treat population also showed an “enormous difference” (HR = 0.60), said Dr. ­Natale, who noted that the median survival had not yet been met, with a median follow-up of about a year.

In contrast, in the phase III CheckMate-026 trial, single-agent nivolumab (Opdivo) showed no significant difference in survival outcome vs a platinum-based doublet in patients with PD-L1 expression greater than 5% (median survival = 14.4 months).3 “In the second-line setting, where nivolumab was compared to docetaxel in patients who had greater than 5% expression, median survival was 18.2 months,” noted Dr. ­Natale. The results of the pivotal trial have left researchers scrambling for answers.

“Some of us believe that the 5% cutoff for PD-L1 expression was too low for this combination study,” said Dr. Natale, who added that the biomarker assay used in the study had not been as rigorously validated as the one used in the pembrolizumab trial. The trial patient population may also have affected the outcome.

Based on the randomized controlled trial of patients with one or two prior lines of treatment, the PD-L1 inhibitor atezolizumab (Tecentriq) has been added to the list of immunotherapy drugs approved in the second-line setting for NSCLC. Patients randomized to atezolizumab showed a 33% relative improvement in survival compared with docetaxel.4 Using Genentech-Roche’s assay, patients were stratified according to PD-L1 status, but no statistically significant difference was found based on expression. “[This was] another biomarker attempt that failed to select out patients with the greatest treatment benefit,” Dr. Natale observed.

Targeting EGFR

Disease progression in advanced NSCLC patients with EGFR mutations inevitably occurs after first-line treatment with either erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif), said Dr. Natale, and usually within 12 months. Laboratory studies and rebiopsy studies have shown that the EGFR T790M point mutation appears to be responsible for the mechanism of resistance in approximately 60% of cases.

Now, based on results of a series of studies, osimertinib (Tagrisso), a potent and highly selective inhibitor of mutated EGFR, has been approved by the U.S. Food and Drug Administration (FDA) and is the treatment of choice for patients with the T790M mutation who have had disease progression following prior therapy with an EGFR tyrosine kinase inhibitor.5

In a small number of treatment-naive patients, the overall response rate and progression-free survival with osimertinib (77%) also appeared to be higher than standard first-line agents.6 According to Dr. Natale, the FLAURA study, a phase III, double-blind, randomized trial of osimertinib as first-line therapy vs gefitinib or erlotinib, should determine the standard of care in this setting.

“Expect osimertinib to be superior,” said Dr. Natale, “although a high proportion of patients in the control arm are expected to cross over to treatment with osimertinib on disease progression.”

Dr. Natale also noted that preliminary data showed activity in patients with central nervous system (CNS) metastases. “There seems to be a very high penetrance of osimertinib into the brain compared to plasma concentrations,” he said. “The development of osimertinib, a mutation-selective targeted agent, is really a major achievement in medical oncology.”

Necitumumab (Portrazza), a human immunoglobulin (Ig)G1 monoclonal antibody designed to target EGFR, was approved in 2015 for first-line treatment of patients with squamous cell carcinoma of the lungs. Necitumumab is similar to cetuximab (Erbitux), said Dr. Natale, and could be considered a biosimilar.

In the phase III SQUIRE study, necitumumab combined with gemcitabine/cisplatin showed a modest increase in overall survival vs gemcitabine/cisplatin alone in patients with stage IV squamous cell NSCLC (HR = 0.84). However, there was a strong trend to better survival in the 35% of patients with high tumor expression of EGFR based on fluorescence in situ hybridization (FISH; HR = 0.74). This observation is consistent with the association of high EGFR FISH expression and improved survival in patients treated with cetuximab and suggests that this biomarker could be used to select patients for treatment. Dr. Natale also noted that a separate study of necitumumab in patients with non–squamous cell lung cancer was closed early due to a high rate of arterial and venous thrombotic problems related to the drug.

“Although this is a modest improvement in survival outcome,” said Dr. Natale, “necitumumab combined with chemotherapy is the first FDA-approved targeted treatment for patients with squamous cell lung cancer.”

Targeting ALK

In December 2015, alectinib ­(Alecensa) was approved for the second-line treatment of patients with ALK-positive NSCLC based on two phase II studies.7,8 In both studies, the response rate for alectinib was close to 50% in patients pretreated with crizotinib (Xalkori).

One of the most important aspects of alectinib’s activity, however, is its efficacy in treating CNS metastases. In patients with baseline measurable CNS lesions, 61% had a response to alectinib. Moreover, said Dr. Natale, CNS responses were observed in patients regardless of prior brain irradiation status, including those who had never received brain irradiation.

Alectinib also has a very favorable toxicity profile compared to any other ALK inhibitors, including ceritinib (Zykadia), which has an overall response rate of 56% and was approved for crizotinib-resistant patients in 2014.9

Dr. Natale suggested that alectinib may soon be the preferred treatment in the first-line setting as well. Presented at the 2016 ASCO Annual Meeting, the phase III J-ALEX study of alectinib vs crizotinib in Japanese patients with ALK-rearranged lung cancer showed a significant improvement in overall progression-free survival compared to crizotinib.10

Disclosure: Dr. Natale’s spouse is an Executive Medical Science Liaison at AstraZeneca.

References

1. Natale R: New therapeutics in lung cancer. 2016 New Therapeutics in Oncology Conference. Presented November 5, 2016.

2. Reck M, Rodriquez-Abreu D, Robinson G, et al: Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. October 8, 2016 (early release online).

3. Socinski M, Creelan B, Horn L, et al: CheckMate 026: A phase 3 trial of nivolumab vs investigator’s choice of platinum-based doublet chemotherapy as first-line therapy for stage IV/recurrent programmed death ligand 1 (PD-L1)-positive NSCLC. 2016 ESMO Congress. Abstract LBA7_PR. Presented October 9, 2016.

4. Barlesi F, Park K, Ciardiello F, et al: Primary analysis from OAK, a randomized phase III study comparing atezolizumab with docetaxel in 2L/3L NSCLC. 2016 ESMO Congress. Abstract LBA44_PR. Presented October 9, 2016.

5. Ramalingam S: Osimertinib as first-line treatment for EGFR mutation-positive advanced NSCLC: Updated efficacy and safety results from two phase I expansion cohorts. 2016 European Lung Cancer Conference. Abstract LBA1_PR. Presented April 14, 2016.

6. Yang J, Ramalingam SS, Jänne PA, et al: Osimertinib (AZD9291) in pre-treated patients with T790M-positive advanced NSCLC: Updated phase 1 and pooled phase 2 results. 2016 European Lung Cancer Conference. Abstract LBA2_PR. Presented April 14, 2016.

7. Ou SI, Ahn JS, De Petris L, et al: Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: A phase II global study. J Clin Oncol. November 23, 2015 (early release online).

8. Shaw AT, Gandhi L, Gadgeel S, et al: Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: A single-group, multicentre, phase 2 trial. Lancet Oncol. December 18, 2015 (early release online).

9. Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 370:1189-1197, 2014.

10. Nokihara H, Hida T, Kondo M, et al: Alectinib versus crizotinib in ALK-inhibitor naive ALK-positive non-small cell lung cancer: Primary results from the J-ALEX study. 2016 ASCO Annual Meeting. Abstract 9008.


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